Beyond KRAS exon 2: Research at ASCO and Important Treatment Implications for Metastatic Colorectal Cancer

By Julie Katz, MPH, M.Phil. and Arnold DuBell, Ph.D.

Introduction

Biomarkers in metastatic colorectal cancer (mCRC) played a prominent role in the research presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting. New data presented at ASCO 2014 showed clinical implications of CRC biomarkers, including the RAS family of mutations. In our post-ASCO discussion, we illustrate the influence of biomarkers on testing and treatment of mCRC, of genetic changes throughout the course of disease, and treatment patterns. These issues have potentially profound implications on a tumor’s behavior and sensitivity throughout the course of the disease. The biomarker research presented represents different approaches to cancer treatment for mCRC.

In 2014, CRC has the fifth highest incidence of all cancers in the United States after breast, prostate, non-small cell lung, and melanoma. Among stage IV incidence cancer cases, CRC is the fourth most common cancer in the United States, behind only non-small cell lung, pancreas, and head and neck. CRC is also the fifth most prevalent disease in the United States (five-year prevalence) behind breast, prostate, melanoma and non-small cell lung cancers. In Western Europe, CRC is the third most frequently diagnosed malignancy and the second most common cause of cancer death, behind lung cancer. In Japan, it is the third most frequently diagnosed malignancy after gastric and lung cancer.

History of EGFR inhibitors and KRAS status

The EGFR monoclonal antibodies, Erbitux® (cetuximab, Bristol-Myers Squibb, Eli Lilly, Merck KGaA) and Vectibix® (panitumumab, Amgen), have been shown to provide differential clinical benefit based on KRAS exon 2 mutational status. Table 2 presents a synopsis of the retrospective clinical data published to date for Erbitux and Vectibix in mCRC patients treated in the first line, according to KRAS status. These data firmly established that EGFR inhibitors, such as Erbitux and Vectibix, provide significant clinical benefit in patients with wild-type KRAS, but that patients with mutant KRAS in exon 2 derive no clinical benefit from these agents.